Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene

in European Journal of Endocrinology
Correspondence should be addressed to M Maghnie or S Perrotta; Email: mohamadmaghnie@gaslini.org or silverio.perrotta@unicampania.it

*(G Patti and S Scianguetta contributed equally to this work)

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Background

Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone.

Aim

To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus.

Patients and methods

We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating.

Results

Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser) and c.215 C>A (p.Ala72Glu) missense mutations and additional eight different mutations previously described were identified; nine were missense and one non-sense mutation. Most mutations (eight out of ten) occurred in the region encoding for the NPII moiety; two mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype–phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed the absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case.

Conclusion

adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.

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Figures

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    Pedigrees of the 13 families (A–M). Affected individuals who underwent genetic testing are indicated by the arrows; circles denote females, squares denote males.

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    Schematic diagram of the coding regions of the vasopressin-neurophysin II gene. The location and type of mutations associated with familial central diabetes insipidus identified are represented and indicated by the arrows.

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    Sequencing chromatograms obtained by automated dye-terminator sequencing of the vasopressin-neurophysin II gene in the patients. A full colour version of this figure is available at https://doi.org/10.1530/EJE-19-0299.

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    Diagnostic flow chart of familial central diabetes insipidus.

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